Chem 345 Reaction List: Chem 343 Reactions: Page 1 (You do not need to know the mechanism for the reactions in the boxes). Nuc- LG Nuc SN2 optically optically active active Alpha carbon (carbon attached to leaving group) must be unhindered. Alpha carbon inverted in the reaction. Leaving group must be good (conjugate pKa less than or equal to 0) Good LG's: I-, Br-, TsO-, etc... More hindered the alpha carbon or the more basic the nucleophile, the more likely that E2 outcompetes SN2. Nuc- LG Nuc SN1 optically racemic active Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo SN1 if a resonance stabilized carbocation is involved. Alpha carbon scrambled in the reaction. Leaving group must be good (conjugate pKa less than or equal to 0) Good LG's: I-, Br-, TsO-, etc... Can undergo rearrangements to give a more stable carbocation. Chem 345 Reaction List: Chem 343 Reactions: Page 2 (You do not need to know the mechanism for the reactions in the boxes). H2SO4 LG E1 optically active Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo SN1 if a resonance stabilized carbocation is involved. The most substituted alkene is the major product (Saitzev's rule) Non-nucleophilic acids like sulfuric acid work best Alcohols are commonly used as leaving groups as sulfuric acid can protonate them to turn them into good leaving groups. Base NOT E2 optically LG active The strength of the base necessary is dependent on the hindrance of the alpha carbon due to competition from the SN2 reaction. Tertiary alpha carbons (no competition with SN2): a moderate base (conj. pKa 10) can be used Secondary alpha carbons: a strong base (conj. pKa 15 or higher necessary) Primary alpha carbons: a strong, bulky base such as KOtBu necessary. Major product dependent on base used. Small base->more substituted alkene. Bulky base (KOtBu)->less substituted alkene. Leaving group and beta hydrogen must be anticoplanar. Leaving group must be good (conjugate pKa less than or equal to 0) Good LG's: I-, Br-, TsO-, etc... HO's cannot be eliminated by an E2 mechanism. Chem 345 Reaction List: Chem 343 Reactions: Page 3 (You do not need to know the mechanism for the reactions in the boxes). PCC (Primary alcohol becomes aldehyde OH CH Cl secondary alcohol becomes ketone. 2 2 O 343 reaction) OH PBr3 Br (Works for methyl, primary, and secondary alcohols via SN2 reaction. Does not react with tertiary R R alcohols. 343 reaction) O R O H2CrO4 (Secondary alcohols are converted or into ketones) 343 Reaction H2O R OH R OH Chem 345 Reaction List: Exam I Reactions: Page 4 (You do not need to know the mechanism for the reactions in the boxes). O RO OR cat. H2SO4 Acid catalyst should be a strong one like TsOH, H SO , or HCl. ROH 2 4 RO OR cat. H SO O 2 4 Acid catalyst should be a strong one like TsOH, H SO , or HCl. H2O 2 4 O R N cat. H2SO4 Acid catalyst can be a weak acid like AcOH. RNH2 R group ends up cis to the smaller substituent on the aldehyde R or ketone. N O cat. H2SO4 RNH2 H2O Acid technically not needed for imine cleavage O cat. NaOH NC OH HCN O KCN NC OH AcOH O acid or base O HO OR acid or base ROH Hemiacetals are mechanistic intermediates only. Very few are stable enough to be synthetic products. Chem 345 Reaction List: Exam I Reactions: Page 5 (You do not need to know the mechanism for the reactions in the boxes). O RMgBr + H3O R OH O O + RLi H3O R OH Organolithiums behave just like Grignards O O NaBH4 H OH EtOH NaBH4 R EtOH R N N H RNH2 cat. AcOH Reductive amination NaBH3CN O R N H O NC OH cat. NaOH About any base capable of pulling a proton off an OH can be used. (conj. pKa 10 or more) O KCN NC NH2 NH Cl 4 Chem 345 Reaction List: Exam I Reactions: Page 6 (You do not need to know the mechanism for the reactions in the boxes). PPh3 (Just an SN2 Reaction) Br PPh3 Base Wittig Reagent PPh3 (Base needs to be strong like PPh3 KOtBu, NaH, NaNH2, or BuLi) O PPh3 Nonstabilized Wittig Nonstabilized Wittigs typically give Z Stabilized Wittigs typically give E O O O PPh3 O O Stabilized Wittig Nonstabilized Wittigs typically give Z Stabilized Wittigs typically give E Mg X MgX (X can be I, Br, or Cl) O 2.0 eq. Li X Li (X can be I, Br, or Cl) (LiX is byproduct) O It is okay if you do not mention 2.0 eq. BuLi RLi RX Lithium Halogen Exchange O (Don't make BuLi this way) Chem 345 Reaction List: Exam II Reactions: Page 7 (You do not need to know the mechanism for the reactions in the boxes). O O (This works when R is methyl or primary sp3 carbon). S 2 reaction RBr R N O O O O cat. H2SO4 (Fisher esterification: This works for methyl, primary, or secondary ROH R OH alcohols but not tertiary alcohols) O O O NaOH OR O O O cat. H2SO4 or cat. NaOR ROH R O O O O cat. H2SO4 Works for tertiary esters (carbonyl oxygen bond remains intact) O OH O O SOCl2 R OH R Cl O O RNH2 R Et3N R N R Cl H O ROH O NEt3 R R Cl R O Chem 345 Reaction List: Exam II Reactions: Page 8 (You do not need to know the mechanism for the reactions in the boxes). DCC O O NEt3 R RNH N OH 2 H O HCl R R H3N O N H O H2/Pd R R H2N O N H O R R H H2N O N N H O O H2/Pd O R HO R Chem 345 Reaction List: Exam II Reactions: Page 9 (You do not need to know the mechanism for the reactions in the boxes). BocCl NHBoc NH2 NEt3 FmocCl NHFmoc NH2 NEt3 ZCl NHZ NH2 NEt3 O O cat. H2SO4 OH O O O H2SO4 N OH H H2O O + O NaOH H3O N H2O H OH O O O NH2 O O N O H O O OH Cl O Chem 345 Reaction List: Exam II Reactions: Page 10 (You do not need to know the mechanism for the reactions in the boxes). O + RMgBr H3O R OH OMe O R O RLi + H3O R OH OMe O R O O excess RMgBr + RH OH O O O excess + O RLi H3O OH O R O + LiAlH4 H3O H OH O excess RMgBr + O H3O CO2 O R OH excess + O RLi H3O CO2 O R R Chem 345 Reaction List: Exam II Reactions: Page 11 (You do not need to know the mechanism for the reactions in the boxes). O LiAlH + 4 H3O OH O OH O LiAlH + 4 H3O O ROH OR OH O + LiAlH4 H3O R R O N N H H LiAlH H O+ N 4 3 O NH2 N RLi + O H3O O R N + RMgBr H3O O O R N O H2SO4 H2O OH Chem 345 Reaction List: Exam II Reactions: Page 12 (You do not need to know the mechanism for the reactions in the boxes). The mechanisms of these reactions are fair game for exam III. Reactions on this page only work on ketones and aldehydes Baeyer-Villiger O O Migration Order: mcpba H>3°C>2°>1°C>Me R' R R' R O O O O O mcpba mcpba H OH O Beckmann HO TsO O NH OH N N O 2 TsCl, NEt HCl 3 Δ R' R R' R R' R N R R' H2O oxime H Migration Order: Whichever group is opposite the O migrates so 3°C>2°>1°C>Me>H O 1.) NH2OH, HCl H 2.) TsCl, NEt3 N H H 3.) Δ, H2O O O O O O Δ 1.) NH2OH, HCl 2.) TsCl, NEt3 NH2OH, HCl 3.) Δ, H2O H2SO4, H2O NH NH Reaction can also be done in a single step. Chem 345 Reaction List: Exam III Reactions: Page 13 OH OD O O excess D D DCl excess DCl D D D NO2 H2SO4 HNO3 O O Cl (Reaction does not work when the ring AlCl3 is strongly deactivated) It can work with halobenzenes, but not anything more deactivated) Cl Br Cl2 Br2 AlCl3 FeBr3 Δ SO H H2SO4 3 H2SO4 SO3 H2O useful way to make ortho substituted benzene rings Chem 345 Reaction List: Exam III Reactions: Page 14 R RCl AlCl3 excess Have to use large excess, otherwise multiple alkylations occur. R is an alkyl group (sp3C). Not a particularly clean reaction as rearrangements occur quite frequently as well. Clemmenson Reduction O HCl ZnHg Ph Ph Reduces ketones and Wolff-Kishner Reduction aldehydes KOH O NH2NH2 Δ Vilsmeier-Haack Reaction POCl3 H2O O DMF O DMF= N H (Reaction does not work when the ring is strongly deactivated) It can work with halobenzenes, but not anything more deactivated) Chem 345 Reaction List: Exam III Reactions: Page 15 Sandmeyer Sequence: H2/Pd/C NH NO2 2 NaNO2, HBr CuBr H2O Br NH 2 N2 Br When using CuBr or CuCl, the acid used in the first step should match. NaNO2, HCl CuCl H2O Cl NH2 N2 Cl CuCN H3PO2 H2O H2O Cl Cl N2 CN N2 H Cu2O KI H2O H2O Cl Cl I N2 OH N2 Chem 345 Reaction List: Exam III Reactions: Page 16 Electrophilic Aromatic Substitution: Approximate Reactivity HO N R O R R R RO O R O R O O R N O R H X S C O N N > > > > > ~ > > > > R=alkyl, aryl X=F, Cl, Br, I If R isn't a carbonyl group, the N can be protonated in strongly acidic media (changing the nature of the Deactivating group) Activating HO N R O R R R RO O R O R O O R N O R H X S C O N N > > > > > ~ > > > > R=alkyl, aryl X=F, Cl, Br, I ortho para directors meta directors para typically favored Chem 345 Reaction List: Exam III Reactions: Page 17 Nucleophilic aromatic substitution NO NO2 2 NaOEt EtOH Cl O If the ring is benzene, then a nitro group has to be present in the ortho or para position to the leaving group.